Career Investigator Award Research Articles

Emerging Trends in Clinical Trial Design

Therefore, randomized trial methodology was initiated only 6 decades ago. As might be expected from such a young field, the pace of advancement remains high. In this editorial, we discuss 3 emerging trends in clinical trial design. The techniques we discuss may be helpful to investigators who are designing randomized trials. They may also be helpful to department leaders who need to allocate resources and guide junior investigators. And finally, an understanding of the methods will also enhance clinicians’ ability to critically read and understand studies on which practice decisions might be based.

Low prevalence of JAK2 V617F mutation in patients with first unprovoked venous thromboembolism

Low prevalence of <i>JAK2</i> V617F mutation in patients with first unprovoked venous thromboembolism

Platelet functions beyond hemostasis, antiplatelet therapies in high-risk patient subgroups: the Fourth Annual Platelet Colloquium

The Fourth Annual Platelet Colloquium (Photo 1), held in Washington, DC January 22–24, 2009, was dedicated to scholarly presentations and open discussions around two overarching themes related to platelet-directed research. The first was emerging knowledge about the role of platelets in vascular integrity, tissue repair, and immune responses. The second concerned the challenges encountered in translating knowledge gained from basic and clinical research into effective treatment strategies for high-risk patient populations, particularly for older patients, women, and patients with selected genotypes. Varied aspects of these two important themes were covered in detail among the five sessions of the Colloquium. The physiological role of platelets encompasses functions beyond their ability to interact together at sites of vascular damage to promote hemostasis and thrombosis. Platelets release inflammatory and angiogenic factors, generate microparticles, serve as a procoagulant surface, and physically and functionally affect immune cells. Platelet activation has been implicated in a variety of systemic disorders such as atherosclerosis, sepsis, acute lung injury, inflammatory conditions, transplant rejection, hepatitis, and heparin-induced thrombocytopenia (HIT), among others. Interactions between platelets, the subendothelial matrix, and leukocytes may also affect the risk of restenosis after percutaneous coronary intervention (PCI). Research continues to examine the effect of different classes of antiplatelet agents on aspects of platelet function beyond inhibition of platelet aggregation and the degree to which antiplatelet therapies may have clinical benefit in conditions other than thrombosis. Research is also addressing well-documented variations in the safety and efficacy of antiplatelet agents according to patient demographic and genetic factors. For example, patients over age 75 have represented nearly 40% of inpatient populations with acute coronary syndromes (ACS) in national registries but only 18% of ACS clinical trial populations. Concerns about the use of antiplatelet therapies in underrepresented high-risk groups have generally focused upon their increased risk of bleeding, which often reflects antithrombotic drug overdosing but could also represent intrinsic aging of platelets, comorbid conditions, hormonal factors, and/or other unknown mechanisms. Conversely, patients with specific genetic mutations that influence metabolism of platelet antagonist drugs, who collectively represented up to 30% of the cohort in one ACS study, show an attenuated in vitro and clinical response to treatment. The true safety and efficacy of various antiplatelet agents in previously underrepresented patient populations can be determined only by increasing their participation in randomized, controlled trials. How best to achieve this important goal was the subject of focused discussion at the Colloquium. The Colloquium also continued its tradition of acknowledging the efforts of creative scientists, both those in the early stages of their careers and those who have made substantial contributions to the field of plateletrelated science. The Early Career Investigator Award (ECIA) is designed to acknowledge the importance of focused scholarly pursuits and mentorship for scientists destined for academic careers in the field of platelet biology. This year’s winner of the ECIA was Henry Sun, MD, of The Johns Hopkins Hospital in Baltimore (Photo 2), who presented his work on glutamate receptors as novel targets of antiplatelet therapy. P. A. French (&) Left Lane Communications, Chapel Hill, NC, USA e-mail: pat.french@leftlanecomm.com

Ecological Studies and Cardiovascular Outcomes Research

Is it better to have a heart attack in the United States or Canada? Ecological studies are epidemiological evaluations in which the unit of analysis is populations, or groups of people, rather than individuals.1 They can answer important questions such as the question posed above that cannot easily be answered using any other form of study design. Ecological studies are conducted by researchers in a variety of disciplines, including outcomes researchers, to study potential causal associations between 1 or more exposure and outcome variables. They are frequently used where alternative study designs are not possible (eg, randomized control trials), such as when investigating the effect of geographical and temporal factors on disease incidence or the effect of a government policy change on health outcomes. In this overview, we provide an introduction to the use of ecological studies in cardiovascular outcomes research, drawing on published examples from our group and others. It is important for clinicians to be aware of both the potential strengths and weaknesses of this type of study design. Because ecological studies are ubiquitous in the medical literature, it is not possible to review all published cardiovascular ecological studies in a systematic manner. Individual-level variables are properties of each person whereas ecological variables are properties of groups, organizations, or places.1,2 All ecological studies are potentially prone to the so-called “ecological fallacy,” which is a term for the biases that may occur when the association that exists between variables at an aggregate level may not represent the true association that exists at an individual level.3 On the other hand, the ecological fallacy may be offset by avoidance of the “individualistic fallacy” whereby one assumes that individual patients are unaffected by the neighborhood in which they live or the setting in which they are treated.4 Complete …

A Candidate Hypertension Gene

See related article, pages 992–999 Hypertension affects >20% of the general population, and yet its etiologic basis remains unknown in the vast proportion of those affected.1 Hypertension greatly increases the risk of stroke, myocardial infarction, congestive heart failure and renal dysfunction thus making it an important focus of clinical research. Although pharmacological reductions in blood pressure have been shown to decrease the incidence of these adverse consequences,2 large numbers of hypertensive patients go undiagnosed, undertreated, or are nonresponsive to lifestyle modifications and medical therapy.1 As such, there remains a pressing need for an improved understanding of the mechanisms underlying hypertension. Recent advances in genomic and proteomic analyses have led to the discovery of Mendelian forms (monogenetic traits) of hypertension.3,4 Although rare, these mutations which mainly involve altered renal salt handling, provide a molecular basis for understanding the critical role of the kidney during normal blood pressure regulation.5 By contrast, our understanding of the relative contributions of kidney, heart, CNS, and blood vessel function to blood pressure variations in the general population is complicated by the fact that spontaneous hypertension typically arises as a complex quantitative trait affected by differing combinations of genetic and environmental factors. A number of quantitative trait loci (QTL) associated with hypertension have been identified in both animal disease models and human patients, however the affected gene(s) at these sites have remained elusive owing to the large size and complexity of the regions identified.6 The use of congenic rodent strains to reduce the genomic size of QTLs is an important advance in the field (Reviewed in 7). Indeed, an article in this issue of Circulation Research highlights the potential of …

Extreme endoscopy: Presidential address

Extreme endoscopy: Presidential address

Role of Pulmonary Surfactant in the Development and Treatment of Adult Respiratory Distress Syndrome

The goal of this article has been to examine the role of pulmonary surfactant system alterations in the development of ARDS, and the potential efficacy of surfactant replacement therapy in ARDS and ARDS-type injuries. Data from patients with ARDS and animal models with ARDS-type injuries clearly indicate the existence of a surfactant-deficient state. However, in contrast to neonatal RDS, this deficiency generally does not represent the primary pathogenic factor. The diversity of the disorders associated with ARDS has made it impossible to develop a single-animal model that can be used to test potential therapeutic measures. The ARDS animal models that have been developed are equally diverse, and represent the wide variations in severity and time-course seen clinically. Nevertheless, almost all of the lung injury models show indications of surfactant abnormality, which is caused mainly by biophysical inhibition of surfactant activity by the large amounts of proteinaceous edema found in the injured lungs. In some cases, this surfactant dysfunction is further compounded by a quantitative surfactant deficiency brought about by metabolic alterations of the type II pneumocytes. It is important to note that all of the lung injury models studied thus far have shown significant improvements in pulmonary mechanics and arterial oxygenation after treatment with exogenous surfactant. Such results are consistent with biophysical studies that suggest that increasing the effective surfactant concentration in the lung should mitigate the effects of both quantitative and functional surfactant deficiencies. Although animal studies suggest that surfactant replacement therapy might be efficacious in ARDS, there is a good deal of experimental work that still needs to be done.(ABSTRACT TRUNCATED AT 250 WORDS)